Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by <b>21</b> has been developed from the initial lead <b>1</b>. Research focused on optimization of a crucial HDM2 Trp23–ligand interaction led to the identification of 2-(trifluoromethyl)­thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors <b>3</b>, <b>10</b>, and <b>21</b> is described

Structure–Activity Relationship (SAR) Optimization of 6‑(Indol-2-yl)pyridine-3-sulfonamides: Identification of Potent, Selective, and Orally Bioavailable Small Molecules Targeting Hepatitis C (HCV) NS4B

A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound <b>4t</b> (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)­pyridine-3-sulfonamide <b>2</b> to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound <b>4t</b> has excellent potency against the HCV 1b replicon, with an EC₅₀ = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound <b>4t</b> has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats